ABSTRACT This study examined externalizing and internalizing behavior problem trajectories as a function of both iron status in infancy and infant characteristics.
A sample of 185 healthy Costa Rican children who either had chronic, severe iron deficiency or good iron status in infancy were followed for 19 years.
Mother ratings of externalizing and internalizing problems from age 5 to 11-14 years were higher for the chronic iron deficiency group compared with those with the good iron status. Iron deficiency in infancy predicted persisting externalizing problems over this time period, especially for those with low physical activity in infancy. Beyond adolescence, youth in the chronic iron deficiency group did not report more problems than those in the good iron group.
These findings underscore the importance of considering infant iron status along with early behavioral characteristics to better identify those children at greatest risk for persisting long-term behavior problems.

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Previous research supports the link among malnutrition, cognitive dysfunction, and behavioral outcomes; however, less research has focused on micronutrient deficiencies. This study investigates whether micronutrient deficiencies, specifically blood zinc and iron levels, will be associated with increased behavior problem scores, including internalizing and externalizing behaviors. 1314 Children (55% boys and 45% girls) from the Jintan Preschool Cohort in China participated in this study. Venous blood samples were collected and analyzed for zinc and iron when the children were 3-5 years old. Behavior problems were measured with the Child Behavior Checklist (CBCL), which was completed by the parents when children were in their last months of preschool (mean age 5.6 years). General linear multivariate modeling was used, with adjustment for important sociodemographic variables. The results indicate that low zinc levels alone (p = 0.024) and combined low zinc and iron levels (p = 0.022) are significantly associated with increased reports of total behavior problems. We did not find an association between low iron and behavior problems. With regards to sociodemographics, living in the suburbs is associated with increased internalizing problems, while higher mother's education and being female were associated with decreased externalizing problems. This study suggests that micronutrient deficiencies and sociodemographic facts are associated with behavior problems in preschoolers.

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Micronutrient deficiencies and suboptimal energy intake are widespread in rural Kenya, with detrimental effects on child growth and development. Sporadic school feeding programmes rarely include animal source foods (ASF). In the present study, a cluster-randomised feeding trial was undertaken to determine the impact of snacks containing ASF on district-wide, end-term standardised school test scores and nutrient intake. A total of twelve primary schools were randomly assigned to one of three isoenergetic feeding groups (a local plant-based stew (githeri) with meat, githeri plus whole milk or githeri with added oil) or a control group receiving no intervention feeding. After the initial term that served as baseline, children were fed at school for five consecutive terms over two school years from 1999 to 2001. Longitudinal analysis was used controlling for average energy intake, school attendance, and baseline socio-economic status, age, sex and maternal literacy. Children in the Meat group showed significantly greater improvements in test scores than those in all the other groups, and the Milk group showed significantly greater improvements in test scores than the Plain Githeri (githeri+oil) and Control groups. Compared with the Control group, the Meat group showed significant improvements in test scores in Arithmetic, English, Kiembu, Kiswahili and Geography. The Milk group showed significant improvements compared with the Control group in test scores in English, Kiswahili, Geography and Science. Folate, Fe, available Fe, energy per body weight, vitamin B12, Zn and riboflavin intake were significant contributors to the change in test scores. The greater improvements in test scores of children receiving ASF indicate improved academic performance, which can result in greater academic achievement.

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The role of diet in the behavior of children has been controversial, but the association of several nutritional factors with childhood behavioral disorders has been continually suggested. We conducted a case-control study to identify dietary patterns associated with attention deficit hyperactivity disorder (ADHD). The study included 192 elementary school students aged seven to 12 years. Three non-consecutive 24-h recall (HR) interviews were employed to assess dietary intake, and 32 predefined food groups were considered in a principal components analysis (PCA). PCA identified four major dietary patterns: the "traditional" pattern, the "seaweed-egg" pattern, the "traditional-healthy" pattern, and the "snack" pattern. The traditional-healthy pattern is characterized by a diet low in fat and high in carbohydrates as well as high intakes of fatty acids and minerals. The multivariate-adjusted odds ratio (OR) of ADHD for the highest tertile of the traditional-healthy pattern in comparison with the lowest tertile was 0.31 (95% CI: 0.12-0.79). The score of the snack pattern was positively associated with the risk of ADHD, but a significant association was observed only in the second tertile. A significant association between ADHD and the dietary pattern score was not found for the other two dietary patterns. In conclusion, the traditional-healthy dietary pattern was associated with lower odds having ADHD.

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Longitudinal Evaluation of Externalizing and InternalizingBehavior Problems Following Iron Deficiency in InfancyFeyza Corapci,1,* PHD, Agustin Calatroni,1MS, Niko Kaciroti,1PHD, Elias Jimenez,3MD, andBetsy Lozoff,1,2MD1Center for Human Growth and Development,2Department of Pediatrics and Communicable Diseases,University of Michigan, and3Hospital Nacional de Nin ˜osObjectiveof both iron status in infancy and infant characteristics.children who either had chronic, severe iron deficiency or good iron status in infancy were followed for 19 years.Results Mother ratings of externalizing and internalizing problems from age 5 to 11–14 years were higher forthe chronic iron deficiency group compared with those with the good iron status. Iron deficiency in infancypredicted persisting externalizing problems over this time period, especially for those with low physical activityin infancy. Beyond adolescence, youth in the chronic iron deficiency group did not report more problems thanthose in the good iron group. ConclusionsThese findings underscore the importance of considering infantiron status along with early behavioral characteristics to better identify those children at greatest risk forpersisting long-term behavior problems.This study examined externalizing and internalizing behavior problem trajectories as a functionMethodsA sample of 185 healthy Costa RicanKey words behavior problems; longitudinal design; infant characteristics; iron deficiency.Iron deficiency anemia (IDA) is the most common singlenutrient disorder, affecting 20–25% of the children world-wide, with a higher proportion of having ID withoutanemia (Stoltzfus, 2001). Recent epidemiological dataalso suggest that 12% of the Hispanic children and 6%of the white and 6% of the African–American children inthe USA have ID (Brotanek, Gosz, Weitzman, & Flores,2007). Infants with ID or IDA generally test lower inmental and motor development and show affective differ-ences (i.e. wariness, hesitance, less positive affect, andless social interaction). Most studies continue to showbehavioral and affective differences after iron therapy(Grantham-McGregor & Ani, 2001; Lozoff et al., 2006).Several studies have found that infants with ID, com-pared with those with good iron status, are more likely toshow poorer mental and motor performance at preschoolor school age (see Lozoff et al., 2006; Thomas, Grant, &Aubuchon-Endsley, 2009 for reviews). Our longitudinalstudy in Costa Rica followed participants from infancy tothe transition to adulthood (19 years) and documentedadverse persisting effects of early, chronic, and severe IDon cognitive performance years later (Lozoff, Jimenez, &Smith, 2006). However, less emphasis has been given tothe long-term social–emotional effects of ID. This oversightis noteworthy because executive cognitive deficits arewidely recognized as a major risk factor for adjustmentproblems (Moffitt & Caspi, 2001). The few available stu-dies showed that children with poor iron status at birthwere significantly less alert and compliant with rules at5 years of age (Tamura et al., 2002). Children in theCosta Rica study described above, who had chronic,severe ID in infancy, displayed lower levels of physicalactivity, positive affect, and verbalization compared withchildren with good iron status in infancy during a struc-tured task at school entry (Corapci, Radan, & Lozoff,2006). Differences in mother-interaction quality (i.e. poormother–child reciprocityandbeyond infancy were also observed (Corapci et al.,2006). The 11- to 14-year assessment of the Costa Ricastudy—the only follow-up study into adolescence—foundthat children with early, chronic, and severe ID were atincreased risk for externalizing (i.e. aggression, defiance)maternalresponsivity)*Present address: Feyza Corapci, Psychology Department, Bogazici University, Istanbul, Turkey; Agustin Calatroni, Rho Inc.,Chapel Hill, North Carolina; Elias Jimenez, Hospital CIMA-San Jose, Costa Rica.All correspondence concerning this article should be addressed to Betsy Lozoff, MD, Center for Human Growth andDevelopment, Department of Pediatrics and Communicable Diseases, University of Michigan, 300N. Ingalls, Ann Arbor, MI48109-0406, USA. E-mail: blozoff@umich.eduJournal of Pediatric Psychology 35(3) pp. 296–305, 2010doi:10.1093/jpepsy/jsp065Advance Access publication September 7, 2009Journal of Pediatric Psychology vol. 35 no. 3 ? The Author 2009. Published by Oxford University Press on behalf of the Society of Pediatric Psychology.All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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and internalizing (i.e. anxiety, depression) problems, asrated by both teachers and parents (Lozoff, Jimenez,Hagen, Mollen, & Wolf, 2000). In several studies, theiron status effect remained statistically significant aftercontrol for child and family background factors.Studyingthedevelopmentalemotional adjustment, especially in countries where theprevalence of ID is high, may help understand how earlyID restricts children from reaching their developmentalpotential (Walker et al., 2007). The concept of ‘‘functionalisolation’’ in the nutrition field has been used to helpexplain long-lasting effects of chronic ID. Accordingto the functional isolation hypothesis (Levitsky, 1979),nutritional deficiencies contribute to changes in infantaffect and activity, which in turn compromise infants’ability to seek and/or receive stimulating and responsiveinteractions from their caregivers, thereby contributing totheir isolation from the environment and poorer develop-mental outcomes over time. Lozoff and colleagues(Lozoff et al., 1998) have offered an integrated biologicaland environmental view of brain–behavior relations. Theypostulated that chronic, severe ID has a direct impacton neurobiological changes in the developing brain(e.g. myelination, neurotransmitter systems, and neuralmetabolism). Given that dopamine and serotonin metabo-lism and functioning are involved in emotion processing,attention, and behavioral activation/inhibition (Beard,2003), alterations in these neurotransmitter systems areof particular relevance to the social–emotional domainand may explain the observed pattern of wariness/hesitance, low activity, and low positive affect observedamong ID infants. The integrated model also includesthe contribution of limitations in caregiving (e.g. lackof responsivity and stimulation) to maintain or evenaccentuate these child characteristics, especially in adisadvantaged environment. Such dynamic, reciprocalinfluences among the neural, social, and ecological factorscombine over time to undermine child self-regulatory com-petence, which refers to the ability to modulate affective,attentional,and motivationalpathways to psychopathology (Posner & Rothbart, 2000).The present study included social–emotional evalua-tions in infancy and four subsequent follow-ups (5, 11–14,15–18, and 19 years) from an ongoing study in Costa Ricato address two novel research questions. First, rather thanexamining the effect of ID on social–emotional functioningat a given point at time, we investigated the pattern ofchange in externalizing and internalizing problems overtime between participants with chronic, severe ID andthose with good iron status in infancy. Second, we exam-ined whether early infant characteristics (e.g. low positivecourseof social–statesand delineatesaffect and activity level) might operate as vulnerability fac-tors in the context of chronic and severe ID. Finally, thepresent study also extended the current knowledge byinvestigating the role of early chronic ID on behaviorproblems beyond early adolescence.Based on the functional isolation hypothesis and pastresearch, we hypothesized that children with chronic ID ininfancy would show persisting levels of externalizing andinternalizing problems from early childhood to adolescenceand beyond, compared with children with good iron statusin infancy. We also predicted that early chronic ID statuswould interact with infant characteristics consistent withfunctional isolation (i.e. higher levels of wary/distressedemotionality, lower activity) to result in greater behaviorproblems over time.MethodParticipantsThe original study was conducted between 1983 and 1985with 191 infants from an urban community near San Jose,the capital of Costa Rica. Enrollment entailed door-to-doorscreening of 12- to 23-month-old infants in the entirecommunity, and refusal was 11.6%. Recruited infantshad a birth weight of ?2.5kg and were free of acuteor chronic medical problems with no evidence of growthfailure or other nutrient deficiencies. At the time of enroll-ment, mothers averaged 26.9 years of age (SD¼6.3)and had 9.6 years of schooling (SD¼3.3). Families weregenerally lower middle to working class. Details of theoriginal study have been published previously (Lozoffet al., 1987).Only 15 participants were completely lost after the5-year follow-up. Fifty-one per cent of the sample hadcomplete social/emotional assessment data in all the fourfollow-up periods (5, 11–14, 15–18, and 19 years). Therest of the participants provided data from a varyingnumber of time points after infancy. Overall, 74% ofthe original sample participated in assessments at both5 years and early adolescence, and 73% of the originalsample participated in assessments at both early andmid-adolescence. Lack of participation in our study wasprimarily due to difficulty in locating a family. The15 participants who were lost after the 5-year follow-updid not differ from the remaining participants with respectto iron status, gender, family socioeconomic status (SES),and behavior problem scores at the age of 5 years (allp-values >.05), suggesting that the sample was notbiased toward those families who were less stressed ortoward those children who were more psychologicallyadjusted. Parental signed informed consent for all phasesBehavior Problems Following Iron Deficiency297

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of the study was obtained by the project pediatrician.Research protocols were approved by the InstitutionalReview Boards of the collaborative institutions.Of the 191 infants in the initial study, six childrenwere excluded due to lack of information about theiriron status after treatment. Fifty-three infants were classi-fied as having chronic ID and 132 were classified as havinggood iron status as described further. At study entry, thechronic ID group had a greater proportion of male infants[73% vs. 46%, Pearson w2(1, N¼142)¼8.06, p<.01]and came from families with significantly lower SESas measuredby the HollingsheadIndex [M¼27.2, SD¼10.8 vs. M¼31, SD¼12.6,t(183)¼?1.9, p?.05]. Of the 151 children (meanage¼60.2 months, range¼59–63 months) assessed atthe 5-year follow-up, 41 of these were in the chronic IDgroup in infancy and 110 were in the good iron statusgroup. Of the 160 children re-evaluated at 11–14 years(mean age¼12.3them were in the chronic ID group. A mid-adolescencefollow-up provided data for 133 participants (meanage¼16.5 years, range¼15.0–17.8); 34 of them belongedto the chronic ID group. An assessment at 19 yearsprovided data for 119 participants (mean age¼19 years,range¼18–20); 34 of them were in the chronic ID groupin infancy.Four Factoryears,range¼10.9–13.7),47ofMeasures and ProcedureIron Status in InfancyAdmission to the study in infancy was based on a venousblood sample. Iron status was determined by concen-trations of hemoglobin (Hb), transferrin saturation,erythrocyte protoporphyrin, and serum ferritin, andresponse to 3 months of iron treatment. Iron statusranged from iron sufficiency to ID with moderateanemia. Iron sufficiency was defined as hemoglobin?120g/l and no abnormal iron measures. Mild anemiawas defined as hemoglobin content 101–105g/l, and mod-erate anemia was defined as hemoglobin content being?100g/l. ID was defined as serum ferritin ?12?g/l, andeither erythrocyte protoporphyrin ?100?g/dl packed redblood cells or transferrin saturation <10%. Infants withhemoglobin <120g/l and ID were given either intramus-cular iron or 3 months of oral iron therapy in two dosesdaily. Infants with hemoglobin ?120g/l who were eitherID or iron depleted (i.e. serum ferritin <12mg/l) receivedoral iron treatment; those with normal values on all ironstatus measures received placebo. Hematologic response toiron therapy in infancy was excellent (Lozoff et al., 1987).However, some infants still had biochemical alterationseven after 3 months of iron treatment (e.g. erythrocyteprotoporphyrin >100?g/dl packed red blood cells ortransferrin saturation ?10%).Analyses reported further compared chronic ID andgood iron status groups based on the approach used inprevious studies of this cohort, beginning with the resultsof the 5-year follow-up (Lozoff, Jimenez, & Wolf, 1991).At 5 years, children who had moderate IDA as infantscontinued to test lower in mental and motor functioning,as did children with higher hemoglobin levels who still hadsome biochemical evidence of ID after iron therapy ininfancy. The same was true in early adolescence; therefore,both groups were combined. They were considered to havesevere and chronic ID in infancy, evidenced by lower initialhemoglobin levels and higher initial erythrocyte protopor-phyrin values. Since anemia is a late manifestation of IDand hemoglobin level reflects chronicity and severity onceanemia develops, infants with moderate IDA had to havechronic, severe ID. Furthermore, enrollment occurred at12–23 months, making it likely that ID had been presentfor some time. The good iron status group consisted ofinfants who were iron sufficient at study entry and thosewith lower hemoglobin and any degree of ID who becameiron sufficient after iron treatment. Iron status of theparticipants was excellent at the 5- and 11- to 14-yearfollow-ups (Lozoff et al., 1991; Lozoff et al., 2000).At the 19-year follow-up, ID was present in <5%, andno one had IDA except for four females, two of whomwere pregnant (Lozoff, Jimenez et al., 2006).Social/emotional Assessment in InfancyMultiple methods and reporters were used to collect socio-emotional data in infancy. First, trained examiners usedthe Infant Behavior Record (IBR) of the Bayley Scales ofInfant Development (Bayley, 1969) with summary scoresbased on prior research (Matheny, 1980; Wolf & Lozoff,1985) to rate infants’ affect and behavior. Second, obser-vers completed quantitative behavior coding of play anddevelopmental testing from videotape to rate the physicalactivity and proximity of the infant to caregiver. All exam-iners were blind to the infant’s iron status or treatment.Inter-rater reliability, assessed by intraclass correlationcoefficient, averaged from 0.88 to 0.93 (Lozoff et al.,1998). Multiple spot observations of infant behavior andaffect were conducted in the home (Rogoff, 1978). Eachapproach distinguished between the chronic ID and goodiron status groups (Lozoff et al., 1998) providing supportfor the measures’ validity.Socioemotional Adjustment from Early Childhoodthrough Early AdulthoodThe Spanish version of the Parent (CBCL), Youth (YSR)and the Young Adult (YASR) forms of the Child Behavior298Corapci et al.

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Checklist (CBC; Achenbach & Edelbrock, 1983, 1991)were used to assess behavior problems. The CBC is avalid and reliable measure that has been used in variouscountries (Crijnen, Achenbach, & Verhulst, 1997). Wecomputed the externalizing and internalizing scale scoresbased on Achenbach’s empirically derived two-factor,second-order structure, which cluster similarly acrosscultures (De Groot, Koot, & Verhulst, 1994, 1996).Maternal ratings on the aggressive and delinquent behaviorsubscales were used for externalizing scale scores at 5- and11- to 14-year follow-ups. Maternal ratings on the socialwithdrawal, somatic complaints, and anxiety/depressionsubscales were used for internalizing scale scores. Aschildren get older, their parents’ evaluations may notreflect the full range of their children’s behavior problems(Leve, Kim, & Pears, 2005). Therefore, at the 15- to18-year and 19-year follow-ups, youth ratings wereobtained. Maternal ratings of the CBCL were not availableat these later follow-ups. Cronbach-a for internalizing andexternalizing scales ranged from .86 to .91 in our sample.All analyses were conducted using t-scores relative to age-normed scores based on the U.S. standardization samplesat each time point.Other MeasuresFamily SES in infancy was assessed using the HollingsheadFour Factor Index (Hollingshead, 1975). Pubertal statuswas assessed with the standard Tanner staging system(Tanner, 1962) during a pediatric examination at the11- to 14-year follow-up. Based on our sample distribu-tion, three levels of Tanner pubertal stages were used indata analysis, i.e. early (Stage 1), middle (Stages 2 and 3),and late (Stages 4 and 5). As part of the 19-year follow-up,participants filled out the Child Health and Illness Profile-Adolescent Edition (CHIP-AE; Starfield et al., 1995) toreport on their school and work performance.Statistical AnalysisInfancy Data ReductionA total of 25 variables pertaining to infant’s affect andactivity, proximity to mother, and engagement with objectscame from examiner ratings on the IBR and from directobservational coding during play and development testingin the clinic and from home observations. An exploratoryfactor analysis was conducted with principle componentanalysis as the extraction method to reduce data andempirically isolate major infancy variables. Orthogonal(varimax) and oblique (promax) rotations were conducted.Both rotations yielded comparable results (r’s between thecorresponding factors produced by varimax and promaxrotations were >.95), and the promax rotation indicatedthat the correlation between the factors was quite negligi-ble. Therefore, we chose to report the findings with theorthogonal rotation to have uncorrelated and moremeaningful factors. The first two factors in the rotatedmatrix pertained to infant affect and activity level andwere retained because they were the most theoreticallymeaningful and interpretable with regard to the functionalisolation hypothesis. These factors accounted for 25% ofthe variance. An affect and inactivity factor score werecomputed using the regression method. A factor loadingof .40 or higher was used. High scores on the affect factorcharacterized infants who were more likely to be wary,upset, tense, unhappy, and easily fatigued during mentaland motor testing and play session. Higher scores on theinactivity factor characterized infants who were less likelyto be walking or playing with objects interactively andmore likely to be asleep or doing nothing during homevisits. These infants were also less likely to explore newareas in play, change their proximal relations to theirmothers as well as vocalize in play, and more likely tobe in a playpen.Longitudinal Data AnalysesLinearmixed(Proc Mixed in SAS) to examine behavior problem trajec-tories depending on iron status in infancy. This approachaccounts for the within subject correlation due to havingrepeated measures (RMs) on the same subjects over timefor externalizing and internalizing problems. It also usesall cases, whether or not they have an equal number ofavailable data across all follow-up periods, and accommo-dates data that are missing at random using a restrictedmaximum likelihood estimation method (Fitzmaurice,Laird, & Ware, 2004). A single growth curve analysisfrom age 5 to 19 years was not possible given the simul-taneous change both in the period of assessment (early tomid-adolescence) and informant (mother to youth).Therefore, two sets of analyses were conducted to modelthe difference between two time points in behavior pro-blems as a function of ID status. The first set includedCBCL ratings at age 5 and 11–14 years per motherreport. The second set of analyses covered the periodfrom age 15–18 to 19 years per youth self-report.To account for the within subject correlation of theCBCL ratings between two observation points, we consid-ered both a random coefficient (intercept) model and RMsapproach using an autoregressive covariance structure.The RM approach had a better fit than the model withrandom intercept based on the Bayesian InformationCriteria (lower BIC value) and was used in the analysis.All analyses included iron status in infancy, time and theirmodels (LMMs)wereimplementedBehavior Problems Following Iron Deficiency299

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interaction as independent variables, and controlling forgender and SES in infancy. Pubertal status was alsoincluded as a covariate when analyzing change in behaviorproblems from 5 to 11- to 14 years. The model examiningchange in behavior problems from age 15–18 to 19 yearsincluded mother ratings of CBCL from age 11–14 years asa covariate. Entering this variable allowed the examinationof the stability of behavior problems over the adolescenceyears (Leve et al., 2005; Sorlie, Hagen, & Ogden, 2008)and also created a conservative test of the unique predic-tive role of ID in infancy, over and above the contributionof behavior problems at early adolescence.ResultsGroup Differences and Change in Mother Ratingsof Behavior Problems from 5 to 11–14 YearsThe two-way interaction term between the iron statusgroup and time was not significant in the LMM analysesof externalizing and internalizing scores. However, therewere significant main effects of iron group and time. Aspredicted, mother ratings of externalizing and internalizingproblems were higher for children in the chronic ID groupcompared with the good iron group, F(1, 174)¼4.9,p<.05, and F(1, 174)¼9, p<.01, respectively (Table I).The direction of change (averaged across iron group) wastoward a decrease in externalizing problems and an increasein internalizing problems over time, F(1, 174)¼15.6,p<.001, and F(1, 174)¼4.2, p<.05, respectively. Thesame pattern of significant findings remained after con-trolling for gender, SES, and pubertal status. As shown inTable I, Cohen’s effect sizes for iron status ranged from .35SD to .54 SD, indicating moderate-sized effects.Change in Behavior Problems from 5 to 11–14Years as a Function of Infant CharacteristicsExternalizing ProblemsTo examine the interactive effect of infant activity level andiron status group on externalizing problems over time, theLMM analysis included a three-way interaction termbetween iron group, time, and infant activity level, alllower order interaction terms, and significant covariates.After covariate control, the three-way interaction termwas significant, F(1, 171)¼6.05, p<.05. To understandthe three-way interaction, the effects of ‘‘high’’ and ‘‘low’’infant inactivity (?1 SD from the mean) on externalizingproblem scores were computed separately for the two-wayinteraction between iron group and time (Aiken & West,1991). As seen in Fig. 1, when infant activity level washigh, children in the chronic ID group improved fromthe subclinical to the normal range (6-point decrease;from a t-score of 64.5 to 58.5), compared with those inthe good iron status, who showed little change (1-pointdecrease; from 58.3 to 57.2). On the other hand, as seen inFig. 2, when infant activity was low, children in the chronicID group remained in the subclinical range of externalizingproblems over time as expected (2-point decrease;Table I. Mother CBCL Ratings of Externalizing and Internalizing Problems at Age 5 and 11–14 years by Iron Status Group in InfancyChronic ID (mean?SD)5Good iron (mean?SD)5Effect size (95% CI)Iron groupTimeAge (years)ExternalizingUnadjustedAdjustedaInternalizingUnadjustedAdjusteda11–14 11–145 11–14FF63.7?963.9?9.360.3?9.760.7?9.960.3?9.660.1?9.956.9?1056.9?9.9.37 (.05–.77).40 (.07–.80).35 (.04–.74).38 (.06–.77)4.9*5.5*15.6***13***64?964.1?9.667.1?9.766.1?9.960.2?10.260.1?10.461.7?10.262.1?10.5.40 (.16–.81).40 (.10–.81).54 (.18–.89).39 (.10–.80)9**6.4**4.2*4.1**p<.05; **p<.01; ***p<.001.aAdjusted values control for gender, SES in infancy, and pubertal status at early adolescence. Adjusted SD was calculated based on SEMˇN.Figure 1. Interaction between iron status and time predicting motherratings of externalizing problems for infants with high activity.300Corapci et al.

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from 63 to 61), whereas those in the good iron groupimproved from the subclinical to the normal range(7-point decrease; from 63.3 to 56.5).In a separate LMM, we also examined the interactiveeffect of infant affect with iron status over time. No suchthree-way interaction was observed for infant affect.Internalizing ProblemsContrary to our expectations, LMM analyses of internaliz-ing scores did not reveal statistically significant two- orthree-way interactions. Main effects for infant activity orinfant affect were also not significant.Group Differences and Change in BehaviorProblems from 15–18 to 19 Years (Self-report)The two-way interaction term between the iron groupstatus and time as well as the main effect of iron groupwere not statistically significant (Table II). These findingsdid not support the expected iron group differences inbehavior problems beyond adolescence. Only the timeeffect was significant; a decrease in externalizing problemsfrom 15–18 to 19 years was detected, before and aftercovariate adjustment,F(1,F(1, 143)¼6.8, p?.01, respectively. After covariate con-trol, a significant decrease in internalizing problems wasalso detected, F(1, 137)¼3.9, p<.05. There were nogender differences in relation to change in either type ofbehavior problems over time. Neither infant activity noraffect had a significant interaction with iron status onthe trajectory of externalizing and internalizing problemsfrom 15–18 to 19 years. There were also no significantmain effects on infant activity or affect.143)¼5.4,p<.05 andExploratory AnalysisWe examined the link between iron status and school andwork performance from the CHIP-EA. We found thata greater proportion of the individuals in the chronic IDgroup dropped out of school in the past 2 years comparedwiththose in the goodw2(1, N¼114)¼4.96, p<.05, Crame ´r’s V¼.21. Therelation between iron status and work productivity wasstatistically marginal, Pearson w2p¼.10, Crame ´r’s V¼.26. Somewhat a larger proportionof young adults in the chronic ID group describedthemselves as inefficient at work compared with theircounterparts.irongroup,Pearson(2, N¼70)¼4.5,DiscussionThe goal of the present study was to examine the change inexternalizing and internalizing problems as a function ofboth iron status in infancy and infant characteristics. Ourinterpretations of both our significant and non-significantfindings are discussed in the following sections.Table II. Youth Self-ratings of Externalizing and Internalizing Problems at Age 15–18 and 19 years by Iron Status Group in InfancyChronic ID (mean?SD)15–18Good iron (mean?SD)15–18Effect size (95% CI)Iron groupTimeAge (years)ExternalizingUnadjustedAdjustedaInternalizingUnadjustedAdjusteda19 19 15–1819FF53.8?8.754.6?8.751.8?8.152.4?8.156.5 (9.6)56.6 (9.6)54.5 (8.5)54.4 (7.7).30 (?.06–.70).22 (?.18–.60).33 (?.04–.74).25 (?.15–.64)3y1.55.4*6.8**55.2?8.155.8?8.153.8?754.2?7.554.7?9.654.7?9.653.3?6.853.1?6.60.06 (–.33—.45).13 (–.29–.49).07(?.33–.46).16 (?.25–.53)0.10.52.9y3.9**p<.10; **p<.05;yp?.01aAdjusted values control for gender, SES in infancy and behavior problems at early adolescence. Adjusted SD was calculated based on SEMˇN.Figure 2. Interaction between iron status and time predicting motherratings of externalizing problems for infants with low activity.Behavior Problems Following Iron Deficiency301

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Early, Chronic ID and Externalizing andInternalizing Problems from 5 to 11–14 Years(Mother Report)Our first set of analyses covered the period from preschoolto early adolescence and included mother ratings ofexternalizing and internalizing problems. Contrary toexpectations, the pattern of change in behavior problemsbetween the chronic ID and good iron groups did not differsignificantly. However, as expected, we found that childrenin the chronic ID group, on average, had higher levelsof externalizing and internalizing problems from age 5 to11–14 years compared with those with good iron status.While we cannot eliminate all possible factor(s) closelyassociated with ID, our results remained significant aftercontrolling for the effects of gender, SES, and pubertalstatus.We also described differences in behavior problemtrajectories as a function of both iron status and infantcharacteristics. Consistent with our predictions, wefound that chronic ID status, when accompanied by lowphysical activity in infancy, predicted persisting externaliz-ing problems from age 5 to 11–14 years, whereas lessactive children in the good iron group showed decreasesin externalizing problems. Conversely, children in thechronic ID group with high activity showed improvementsin externalizing problems. Finally, children in the goodiron group who were active infants remained in thenormal ranges at both ages.The current findings make sense in the framework ofthe functional isolation model (Levitsky, 1979) and theintegrated biological/environmental model (Lozoff et al.,1998). In line with the predictions of these models, wefound that chronic ID in infancy contributed to long-last-ing behavior problems, possibly through the interplay ofintermediary neural and environmental mechanisms.The investigation of such mediating mechanisms wasbeyond the scope of the present study, but we can specu-late that the brain effects of ID have contributed todopamine-related behaviors such as infant inactivity(Beard, 2003).However, a child’s activity level partly dependson parental behavior and thus may not be the resultof ID per se. In fact, previously published reports ofthe infancy cohort and the 5-year follow-up sample ofthe Costa Rica study provide evidence for the lackof warmth and responsivity in the mother–child interac-tions of children with ID in infancy (Corapci et al.,2006; Lozoff et al., 1998). These observations pointto the highly interactive and transactional influences ofchildand caregiving characteristics(Sameroff&MacKenzie, 2003; Wright, 2008). Based on the con-temporary theories of child development and empiricalevidence, there is an increasing recognition that nutri-tional deficiencies are translated into child behaviorproblems through such developmentally inhibiting trans-actional processes, which in turn appear to underminethe development of children’s self-regulatory skills suchas the ability to modulate affect, attention, and behavior(Wachs, 2009; Wachs, Pollitt, Cuerto, Jacoby, & Creed-Kanashiro, 2005).The importance of ‘‘child effects’’ as a starting point inthe transactional processes in the case of ID in infancy hasbeen documented in preventive trials, animal studies anddevelopmental testing observations. Large randomized,controlled preventive trials (Black et al., 2004; Lozoff,De Andraca, Castillo, Smith, Walter, & Pino, 2003)provided evidence that a greater percentage of the infantswho did not receive iron supplementation showed lesspositive affect and poorer social interaction comparedwith iron-supplemented infants. These results suggestthat the lack of iron in infancy causes alterations ininfant affect and interaction, independent of child orfamily differences. Animal research has shown thatmonkey infants on prenatally iron-deprived diets showedreduced activity (Golub, Hogrefe, Germann, Capitano, &Lozoff, 2006). Furthermore, in the infancy phase of theCosta Rica study, the tester, who was uninformed aboutthe infants’ hematologic status, offered fewer demonstra-tions and encouragements to IDA and comparison groupinfants during developmental testing, indicating thatadults other than the mother behaved differently withthese infants.Our findings also suggest that in the context of lowerenvironmental risk for the good iron group, caregiversmight have been more likely to perceive their low-activitychildren as ‘‘easy’’ babies and promote the development ofself-regulation in their children with adequate monitoring,effective disciplining, and modeling of emotion andbehavior regulation, thereby diminishing the likelihood ofexternalizing problems. In contrast, being an active infantemerged as a buffering factor for those infants in thechronic ID group and led to decreases in externalizingproblems from age 5 to 11–14 years. It is possible thatthese active children were more likely to elicit parentalattention and involvement. It is also possible that parents,who were informed about their children’s ID status atthe end of the infancy study, might have perceived theirhighly active and chronic ID children at risk for laterproblems and thus might have been more sensitive totheir children’s cues.302Corapci et al.

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Early, Chronic, Severe ID, and Externalizing andInternalizing Problems from 15–18 to 19 Years(Youth Self-report)Our second set of analyses covered the period frommid-adolescence to early adulthood and included youthself-ratings of externalizing and internalizing problems.The pattern of change in behavior problems from age15–18 to 19 years was the same for each iron groupstatus. Contrary to our expectations, youth in the chronicID group reported problems in the normal range, as didthose in the good iron group. Since behavioral ratings werenot obtained from other informants after early adolescence,we do not know whether the association between early,chronic ID and behavioral adjustment detected earlyon dissipated by late adolescence or whether the lack ofassociation was due to change in informant.In contrast to the lack of differences in behaviorproblems in late adolescence, recent findings from thissample revealed differences in cognitive test scores frominfancy to 19 years. The gap between the good iron statusand ID group widened, especially for those childrencoming from low-SES families and reached a magnitudeof 25–28 points of difference (Lozoff, Jimenez et al.,2006). It seems likely that a cumulative cognitive deficitof the observed magnitude would impair self-regulation,verbal reasoning and executive functioning, and thuswould contribute to impulsive responding, inattention aswell as poor planning, thus increasing the risk for psycho-pathology (Moffitt & Caspi, 2001; Pennington & Ozonoff,1996). It is possible that cognitive limitation in the chronicID group compromised the reliability and quality of theirself-report. In our exploration of the real-life impactsin early adulthood of ID in infancy, we found a higherprevalence of school dropout and work unproductivity at19 years in the chronic ID group. This finding makesa fading effect of ID less likely and again suggeststhat informant bias may have contributed to the lack ofdifference in behavior problems by self-report.A discrepancy between parent and youth reportedexternalizing and internalizing problems has been reportedfor children with low birth weight (Saigall, Pinelli,Hoult, Kim, & Boyle, 2003). Significant differences weredetected between the groups based on parent report, butnot based on youth self-report. Differences in parent andchild reports of behavior problems have also been docu-mented in previous clinical psychology research. Youth,compared with their parents, under-report problems,perhaps due to failure to acknowledge their problemsor embarrassmentabout(Achenbach, Krukowski, Dumenci, & Ivanova, 2005;revealingtheir problemsJensen et al., 1999; Martin, Ford, Dyer-Friedman, Tang,& Huffman, 2004).Limitations, Conclusions, and Future ResearchThe lack of behavioral ratings from other informants afterearly adolescence is a limitation of our study. Thus, a singlegrowth curve analysis was not possible to use to examinethe developmental trajectory of behavior problems becausewe could not tell whether differences from early to mid-adolescence related to actual changes in behavior problemsor to their measurement (i.e. mother- vs. self-report).Although long-term effects of early, severe and chronicID on behavior problems beyond early adolescence werenot detected per youth self-report, this finding should beconsidered tentative in light of cognitive impairments andfunctional outcomes and be replicated in future research.Future studies with multiple reporters and multiplemeasures of impairment (both objective and subjective)are warranted to differentiate a potential waning influenceof early iron status from self-report biases.A causal relationship between chronic, severe ID ininfancy and behavioral problems cannot be provedalthough iron group differences from age 5 to 11–14years remained significant after control for child andfamily background variables. Some uncontrolled or unmea-sured factor(s) closely associated with ID might accountfor the group differences. Another limitation is that there isno study comparable with our multi-method approach forsocial–emotional data in infancy, and hence there is nopossibility of direct comparisons regarding our data reduc-tion. It is thus unclear whether our findings are general-izable to other samples, including children who are nothealthy or full term. Furthermore, we know relativelylittle about how early ID impacts the immediate socialcontext. For example, mother–child interactions arecentral to the transactional framework of the functionalisolation hypothesis and suggest not only an importantmediating mechanism but also avenues for intervention.Future research should test models that include parent–child interaction measures as time-varying covariates inorder to better understand how the level of behaviorproblems following early, chronic ID changes in relationto changes in caregiving quality.In conclusion, our findings suggest that chronic ID ininfancy represents a risk factor for later behavior problemsand chronic ID along with infant inactivity identifies chil-dren at greatest risk for long-lasting externalizing problemsfrom early childhood to early adolescence. These resultsraise the question of whether the pediatric evaluation ofchildren with ID should include an assessment of child’sbehavioral and affective characteristics within the socialBehavior Problems Following Iron Deficiency303